Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][C:15](OCC)=[O:16]>CN(C)C=O.O>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([N:1]2[CH2:12][CH2:13][CH2:14][C:15]2=[O:16])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: CCOC(=O)CCCBr
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Yield: 66.8 %

Procedure:
A solution of 4-aminobenzoic acid (Aldrich, 3.0 g, 21.9 mmol) and ethyl 4-bromobutyrate (Aldrich, 6.4 g, 32.8 mmol) in 20 mL of dimethylformamide was stirred at reflux for 24 h. The solvent was removed under vacuum to give a crude solid which was suspended in 15 mL of water, collected by filtration and dried. The solid was suspended in a small amount of ether (5 mL), filtered and dried to give 3.0 g (66%) of the title compound as a white solid, mp 244-246° C. (ether/ethanol), lit.mp 244-245° C. [Hopff et al. Ger. 859, 007, Sep. 22, 1952; Chem. Abstr. 52 11124h (1958)].
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[OH:4])[CH3:2].[C:7]1([N:13]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]2=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([N:13]2[C:17](=[O:18])[CH2:16][CH:15]([O:4][N:3]([CH2:5][CH3:6])[CH2:1][CH3:2])[C:14]2=[O:19])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1C=CC(=O)N1c1ccccc1
Reactant: CCN(O)CC
Product: CCN(CC)OC1CC(=O)N(c2ccccc2)C1=O

Procedure:
The procedure of Example 1 is repeated using 4.46 g (50 mmole) of N,N-diethylhydroxylamine and 8.66 g (50 mmole) of N-phenylmaleimide.
Reaction SMILES: [CH3:1][C@H:2]([N:5]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]#[CH:4].[N:24]([Si](C)(C)C)=[N+:25]=[N-:26]>CN(C=O)C.CO.[Cu]I>[N:24]1[NH:25][N:26]=[C:3]([C@@H:2]([N:5]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH3:1])[CH:4]=1
Reactant: C#C[C@H](C)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](c1cn[nH]n1)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 79 %

Procedure:
A mixture of (S)-tert-butyl but-3-yn-2-yl(3-((tert-butoxycarbonyl)amino)propyl)carbamate (710 mg, 2.18 mmol), azidotrimethylsilane (452 μl, 3.26 mmol) and copper (I) iodide (21 mg, 0.11 mmol) in DMF/MeOH (1:1, 3.4 mL) was heated to 100° C. for 8 h. Upon cooling, the mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo and purified via silica gel chromatography (EtOAc-Heptane, 30-80%) to afford the title compound (636 mg, 79%) as an oil. LCMS: Rt=0.78 min, m/z=370.1 (M+1) Method 2m_acidic.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].O.[C:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>CC(C)=O>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[C:11]([OH:13])=[O:12])=[O:24])=[CH:26][CH:27]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Nc1ccc(C(=O)O)cc1C(=O)O
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2C(=O)O)cc1
Temperature: 25 °C
Yield: 28.7 %

Procedure:
Into 60 mL acetone was dissolved 0.905 g (5 mmol) 4-aminoisophthalic acid. To the solution was added 30 mL water. The mixture was cooled in an ice bath, and 1.08 mL (5.5 mmol) 4-tert-butylbenzoyl chloride in 10 mL acetone was added dropwise. The mixture was allowed to warm slowlyly to room temperature and after 24 h was concentrated under vacuum and shaken between EtOAc (150 mL) and cold dilute HCl (150 mL). The organic layer was dried (MgSO4) and evaporated. The desired crystalline product (0.489 g, 29%) was obtained from methylene chloride-hexane.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.ClC1C=C(SC2N(CC(F)(F)F)C(CO)=[N:36]C=2C(C)C)C=C(Cl)C=1>>[NH2:36][CH2:2][C:3]1[N:4]([CH2:20][C:21]([F:22])([F:24])[F:23])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1
Reactant: CC(C)c1nc(CO)n(CC(F)(F)F)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1nc(CCl)n(CC(F)(F)F)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CN)n(CC(F)(F)F)c1Sc1cc(Cl)cc(Cl)c1

Procedure:
2-Chloromethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(2,2,2-trifluoroethyl)-1H-imidazole (28k)was synthesized from [5-(3,5-dichlorophenylthio)-4-isopropyl-1-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl]methanol (Compound I-33)by the same synthetic process as that for (28a)in Example 66, and without purification of this compound, 2-azidomethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(2,2,2-trifluoroethyl)-1H-imidazole (29k)was obtained by the same synthetic process as that for (29a)in Example 66. Oil.
Reaction SMILES: [CH3:1][Li].[Si:3]([O:10][CH2:11][C@H:12]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:13]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl-].N.[OH-].N>CCOCC>[Si:3]([O:10][CH2:11][C@@H:12]([NH:13][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:14]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH3:1])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: [Li]C
Reactant: CC(C)(C)OC(=O)N1[C@H](c2ccc(C(F)(F)F)cc2)[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: N
Agent: [Cl-]
Agent: [OH-]
Solvent: CCOCC
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a stirred slurry of cuprous iodide (7.9 g, 42 mmol) in 150 mL ether at 0° C. was added methyllithium (1.6 M solution in diethyl ether (52 mL, 83 mmol)). The mixture was stirred at this temperature for 20 minutes. A solution of (2R,3R)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-(4-(trifluoromethyl)phenyl)aziridine-1-carboxylate (6.00 g, 14 mmol) in 150 mL ether was then added via cannula to the lithium dimethylcuprate solution. The mixture was stirred at 0° C. and monitored by TLC. When no starting material could be detected (about 7 hours), 250 mL of an 8:1 mixture of saturated aqueous ammonia chloride and ammonia hydroxide (28-30% in water) was added to the reaction. The resulting reaction mixture was extracted with diethyl ether (2×300 mL). The combined organic layers were washed twice with brine and dried over sodium sulfate. The crude product was then chromatographed eluting with 3% EtOAc in hexane. After removing the solvent, the desired product was obtained as a colorless oil (2.0 g, yield=32%). 1H NMR (400 MHz, CD3OD) δ ppm 0.09 (s, 6 H) 0.90-0.96 (m, 9 H) 1.25-1.33 (m, 12 H) 3.00-3.11 (m, 1H) 3.68-3.80 (m, 3H) 7.43 (d, J=8.02 Hz, 2H) 7.56 (d, J=8.02 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25]N)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3[C:23]4[C:22](=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=4)[NH:25][C:9]=3[C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3ccc([N+](=O)[O-])cc3c1C2

Procedure:
Under the same conditions as the method for synthesizing Compound A3-1, the title compound was prepared from Compound A2 and 4-nitrophenylhydrazine.
Reaction SMILES: [O:1]=[C:2]([CH2:24][CH3:25])[CH2:3][C:4]([NH:6][C@@H:7]1[C:22](=[O:23])[N:9]2[C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[CH2:12][S:13][C@H:8]12)=[O:5].C(O)(=O)C.[N:30]([O-])=[O:31].[Na+]>O>[OH:31][N:30]=[C:3]([C:2](=[O:1])[CH2:24][CH3:25])[C:4]([NH:6][C@@H:7]1[C:22](=[O:23])[N:9]2[C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[CH2:12][S:13][C@H:8]12)=[O:5]
Reactant: CCC(=O)CC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)C(=NO)C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12

Procedure:
To a solution of 6 g. of benzhydryl ester of 7β-(3-oxovaleramido)-3-acetoxymethylceph-3-em-4-carboxylic acid in 20 ml. of glacial acetic acid are added dropwise 1.54 g. of sodium nitrite dissolved in 15 ml. of water, and the mixture is stirred for 2 hours at ambient temperature. The mixture is then diluted with 500 ml. of ethyl acetate and washed 3 times with 100 ml. of an aqueous saturated sodium chloride solution. The organic phase is made anhydrous and evaporated to dryness and the residue is triturated with diethyl ether. 5.5 g. of benzhydryl ester of 7β-(2-hydroxyimino-3-oxovaleramido)-3-acetoxymethylceph-3-em-4-carboxylic acid melting at 56°-62° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][C:6]=2[C:5](=[O:21])[N:4]([CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:3]1=[O:32].[OH:33]O>CO>[OH:33][C:10]1[CH:9]=[N:8][C:7]2[N:2]([CH3:1])[C:3](=[O:32])[N:4]([CH2:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:5](=[O:21])[C:6]=2[CH:11]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Reactant: OO
Solvent: CO
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(O)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of 1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.8 g, 6.3 mmol) in MeOH (100 mL) at 0° C. was added H2O2 (30% in water, 1.4 mL, 10.6 mmol) dropwise over 5 min. The reaction was allowed to warm slowly to RT, stirred for 16 h, quenched with aq. 1M Na2SO3 solution (100 mL), stirred for 15 min then extracted with EA (3×75 mL). The combined organic layers were dried over Na2SO4 and concentrated to give a residue of 6-hydroxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.1 g, 100% yield) as a solid. LCMS: [MH+-THP] 252 and TR=1.740 min. Used without further purification.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][CH:7]=[CH:6][CH:5]=1.[N+:9]([C:12]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[Cl:37])=[CH:22][C:13]=1[O:14][CH:15]([CH2:19][CH2:20][CH3:21])[C:16](Cl)=[O:17])([O-:11])=[O:10]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[O:8][CH:7]=[CH:6][CH:5]=1)[C:16](=[O:17])[CH:15]([O:14][C:13]1[CH:22]=[C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:29][C:28]=2[Cl:37])[CH:24]=[CH:25][C:12]=1[N+:9]([O-:11])=[O:10])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: CNCc1ccco1
Solvent: ClCCl
Product: CCCC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)N(C)Cc1ccco1
Temperature: -15 °C

Procedure:
N-Methyl-N-furfurylamine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]pentanoyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. This residue is then purified by subjecting it to elution chromatography using mixtures of ethyl acetate and hexane with increasing concentrations of ethyl acetate as the eluant. The desired fractions determined by IR spectroscopy are then stripped of solvent to yield the desired product N-methyl-N-furfuryl-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]pentanamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=3)=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:23][NH:24][O:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([N:24]([O:25][CH3:26])[CH3:23])=[O:21])=[CH:17][CH:18]=3)=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CNOC
Reactant: CC1(C)Cc2c(COc3ccc(N=C=O)cc3)cccc2O1
Solvent: Cc1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCc2cccc3c2CC(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
1.8 g of 4-(2,3-dihydro-2,2-dimethyl-4-benzofuranylmethyloxy)phenyl isocyanate was dissolved into 20 ml of toluene, and 2.0 g of N,O-dimethylhydroxylamine dissolved in 5 ml of toluene was slowly added dropwise thereto at room temperature. After the mixture was stirred at room temperature for 2 hours, toluene was distilled off and the residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/4) as a developer to obtain 1.8 g of Compound No. 6 shown in Table 1.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:11][C:10](B(O)O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].Br[C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:28]1[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:1]([NH:5][CH2:6][C:7]1[S:11][C:10]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:28]2[CH2:29][CH2:30][N:31]([S:34]([CH2:37][CH3:38])(=[O:35])=[O:36])[CH2:32][CH2:33]2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 24 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), butylamine (24 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 49 mg of crude {5-[(butylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(butylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 27.2 mg of the title compound (24%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.CN1CCOCC1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>C(#N)C>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:15]=[CH:16][C:3]([CH2:2][NH:1][C:24](=[O:27])[CH2:25][CH3:26])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: CCC(=O)Cl
Reactant: NCc1ccc(Oc2ccc(O)cc2)cc1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCC(=O)NCc1ccc(Oc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-(4-Aminomethyl-phenoxy)-phenol (0.10 g, 0.47 mmol), MMP-resin (polystyrene bound N-methylmorpholine-type base, 0.30 g, 1.04 mmol) and 1.9 mL of acetonitrile was treated with propionyl chloride (0.086 mL, 1.0 mmol) and shaken for 24 hours at room temperature. After filtration of the resin, the filtrate was diluted with 2 mL of methanol and was treated with 2 mL of 1M lithium hydroxide (LiOH) in water. The mixture was shaken for 24 hours at room temperature, treated with Amberlite IRP-64® resin until neutral, filtered and concentrated in vacuo, affording N-[4-(4-Hydroxy-phenoxy)-benzyl]-propionamide. MS (m/z): 272.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([OH:14])=[CH:9]2)([O-:3])=[O:2].I[CH3:16]>>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([O:14][CH3:16])=[CH:9]2)([O-:3])=[O:2]
Reactant: CI
Reactant: O=[N+]([O-])c1cccc2cc(O)cnc12
Product: COc1cnc2c([N+](=O)[O-])cccc2c1
Yield: 26 %

Procedure:
In a manner analogous to that described in Example 30 a) the alkylation of the 8-nitro-quinolin-3-ol (CAS25369-37-3) with iodomethane yielded the title compound as a yellow solid (yield 26%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[N:10]1[CH:15]=[CH:14][N:13]=[C:12]2[C:16]([O:18][C:19](=[O:20])[C:11]=12)=[O:17].[NH4+].[Cl-]>CCOCC.C1COCC1>[CH3:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:16]([C:12]1[C:11]([C:19]([OH:18])=[O:20])=[N:10][CH:15]=[CH:14][N:13]=1)=[O:17]
Reactant: O=C1OC(=O)c2nccnc21
Reactant: Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C(=O)c2nccnc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The Grignard reagent from 8.5 g (50 mmol) 3-bromotoluene and 1.2 g magnesium in 50 ml ether was added dropwise at 0°-10° C. to a solution of 7.5 g (50 mmol) pyrazine-2,3-dicarboxylic acid anhydride in 100 ml THF and after completed addition, the solution that formed was stirred for 4 hours at room temperature. 500 ml cold, saturated NH4Cl solution was then added, it was extracted with ethyl acetate and the organic phase was dried, concentrated by evaporation and purified as in example 1a and 2a. Yield 4 g (32% of theoretical yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[C:21]1([NH:27][C:28](=[N:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)SC)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:32]1([NH:31][C:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CSC(=Nc1ccccc1)Nc1ccccc1
Reactant: NCCCCCCCCOc1ccc2ccccc2c1
Product: c1ccc(N=C(NCCCCCCCCOc2ccc3ccccc3c2)Nc2ccccc2)cc1

Procedure:
4.0 g of 1-amino-8(2-naphthyloxy)octane and 3.6 g of 1,3-diphenyl-S-methylisothiourea were heated to 110° C. under a nitrogen atmosphere for 3 hours. The crude product was chromatographically separated from the reaction mixture on a silica gel column with the mobile phase being methylene chloride:methanol:ammonium hydroxide 100:12:1.2 thereby isolating the 1,2-diphenyl-3-[8-(2-naphthyloxy)octyl]guanidine which was converted to the hydrochloride (mp 124°-126°) using the procedure of Example IV.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[C:7]([CH3:20])=[CH:8][N:9]2[C:14]=1[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:10]2)=O>O1CCCC1>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C:6]1[C:7]([CH3:20])=[CH:8][N:9]2[C:14]=1[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:10]2
Reactant: CCOC(=O)c1ccn2cc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccn2cc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 59.3 %

Procedure:
Ethyl 1-(2,4-dichorobenzoyl)-2-methylindolizine-7-carboxylate (3.17 g) was dissolved in tetrahydrofuran (32 ml), and a 10M borane-dimethyl sulfide complex (9.5 ml) was dropwise added under ice-cooling. The mixture was stirred at room temperature for 3.5 hr, neutralized and partitioned between ethyl acetate and water. The organic layer was washed three times with water and then with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=19/1) to give the objective compound (1.81 g) as a pale-yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.O[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:40])[CH:25]([N:27]2[CH2:32][CH2:31][C:30]([OH:39])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)[CH3:26])=[CH:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:39][C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:31][CH2:32][N:27]([CH:25]([CH3:26])[C:24]([C:21]2[CH:20]=[CH:19][C:18]([O:13][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][C:8]([CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:9][CH:10]=3)=[CH:23][CH:22]=2)=[O:40])[CH2:28][CH2:29]1
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Reactant: CC(C(=O)c1ccc(O)cc1)N1CCC(O)(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C(=O)c1ccc(OC(=O)c2ccc(CN3CCOCC3)cc2)cc1)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a mixture of 4-(morpholinomethyl)benzoic acid (3.17 g, 12.3 mmol), 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanone (4.0 g, 12.29 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (2.36 g, 12.31 mmol) in methylene chloride (75 mL) was added 4-dimethylaminopyridine (1.88 g, 15.39 mmol). The heterogeneous mixture was allowed to stir overnight under a nitrogen atmosphere at ambient temperature. The mixture was washed with saturated aqueous bicarbonate (2×50 mL), dried by filtration through phase separating filter paper, and concentrated to a glassy yellow solid. Trituration with ether and hexane yielded 5.17 g, 80% of a light yellow solid product which was suitable for further reaction without additional purification. A sample recrystallized from ethyl acetate/hexane had: m.p. 126°-126.5° C.; NMR (CDCl3) 8.22 (d, J=8.6 Hz, 2H), 8.13 (d, J=7.8 Hz, 2H), 7.47 (t, J=7.3 Hz, 4H), 7.34-7.19 (m, 5H), 4.13 (q, J=6.6 Hz, 1H), 3.70 (t, J=4.4 Hz, 4H), 3.57 (s, 2H), 2.97-2.79 (m, 2H), 2.67-2.60 (m, 2H), 2.44 (t, J=4.5 Hz, 4H), 2.18-1.98 (m, 2H), 1.78-1.67 (m, 3H), 1.31 (d, J=6.6 Hz, 3H). IR (KBr) 3270, 2960, 2942, 2912, 2830, 2821, 1743, 1682, 1596, 1390, 1273, 1199.