Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=[CH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=2[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2
Reactant: O=C1c2ccccc2C(=O)N1CCCC1c2ccccc2C=Cc2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCC1c2ccccc2C=Cc2ccccc21

Procedure:
5-(3-Phthalimidopropyl)-5H-dibenzo[a,d]cycloheptene, 2.15 g. (0.0054 mole), is dissolved in 50 ml. of hot 95% ethanol. Hydrazine hydrate, 0.6 ml., is added and the solution heated to refluxing for 2 hours. The solution then is cooled, acidified, and the precipitate of phthalhydrazide removed by filtration. Ethanol is distilled from the filtrate under reduced pressure and the residue dissolved in 40 ml. of water. The filtered solution is evaporated by heating under reduced pressure to a volume of approximately 20 ml. Upon cooling, the hydrochloride salt of 5-(3-aminopropyl)-5H-dibenzo[a,d]cycloheptene is precipitated in a yield of 1.35 g. (87.5%). After recrystallization from a mixture of ethanol and ether and from isopropyl alcohol, an analytical sample melted at 263°-265°C., dec.
Reaction SMILES: [NH2:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[Cl:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[CH3:18][O:17][C:15]([C:2]1([NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][Cl:25])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1)=[O:16]
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1(NC(=O)CCCCl)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-amino-1-BOC-piperidine-4-carboxylate (2.0 g, 6.78 mmol) in DCM (15 mL) and pyridine (2.10 mL, 20.35 mmol), 4-chlorobutyryl chloride (0.84 mL, 7.5 mmol) in DCM (5 mL) was added slowly at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with DCM (40 mL), and quenched with saturated NaHCO3 (30 mL). The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were then washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated to give 4-(4-chloro-butyrylamino)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester which was used further without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CO.C(Cl)Cl.Cl[Pd]Cl>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2cccc(C(F)(F)F)c2)c1
Temperature: 100 °C
Yield: 73.5 %

Procedure:
Methyl 2-bromoisonicotinate (2.71 g, 12.57 mmol), 3-(trifluoromethyl)phenylboronic acid (3.58 g, 18.85 mmol), potassium carbonate (2.61 g, 18.85 mmol) and PdCl2 (dppf) (0.162 g, 0.25 mmol) were mixed in methanol (30 mL) in two 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. DCM and water were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a brown solid. The residue was dissolved in DCM and added onto an SCX-2 cation exchange column. The column was washed with DCM, MeOH and then eluted with NH3/MeOH (1 CV each). The NH3/MeOH layer was evaporated yielding methyl 2-(3-(trifluoromethyl)phenyl)isonicotinate (2.6 g, 73%). MS m/z 282 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15]CC)=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][NH2:19]>CCO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([NH:18][NH2:19])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(F)c2)on1
Reactant: NN
Solvent: CCO
Product: NNC(=O)c1cc(-c2cccc(F)c2)on1
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of ethyl 5-(3-fluorophenyl)isoxazole-3-carboxylate (25.8 g, 110 mmol, 1.0 equiv.) in EtOH (300 mL), was added hydrazine (10.5 mL, 330 mmol, 3.0 equiv.). The mixture was stirred at 80° C. for 1 h and then cooled to RT The precipitate was filtered, washed with H2O, and dried in vacuum to give 5-(3-fluorophenyl)isoxazole-3-carbohydrazide (20 g). The filtrate was concentrated and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give desired product (2.5 g). LRMS (M+H+) m/z 222.0.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br.[CH2:18]([O:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30]Br)[CH2:24]1)=[O:22])[CH3:19].O>C1(C)C=CC=CC=1>[CH2:18]([O:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:24]1)=[O:22])[CH3:19]
Reactant: Oc1ccccc1Cc1ccccc1
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(CCOc2ccccc2Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
Sodium hydride (0.8 g, 20 mmol, 60% oil dispersion) was added portionwise to a stirred solution of 2-benzylphenol (1.8 g, 10 mmol) in toluene (30 ml) placed under an atmosphere of nitrogen. The mixture was stirred for 30 minutes and (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (3.5 g, 10 mmol, EP 374801) was added portionwise. The reaction mixture was stirred for 2 h at ambient temperature and water (50 ml) was added. The phases were separated and the organic phase was extracted with a 10% citric acid solution (200 ml). This acidic solution was extracted with a small portion of toluene and the organic extracts were discarded. To the acidic aqueous phase 4N sodium hydroxide was added until pH 7-8 and the mixture was extracted with ethyl acetate (150 ml). The organic extract was dried (Na2SO4) and the solvent was evaporated in vacuo to give 1.7 g of (R)-1-(2-(2-benzylphenoxy)ethyl)-3-piperidine-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]1)=[O:4].[OH:13][NH2:14].C(N(CC)CC)C.Cl.ON>CS(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](=[NH:12])[NH:14][OH:13])[CH2:7][CH2:6]1)=[O:4]
Reactant: NO
Reactant: COC(=O)C1CCC(C#N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)C1CCC(C(=N)NO)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
A mixture of 4-cyano-cyclohexanecarboxylic acid methyl ester (1070 mg, 6.40 mmol), N-hydroxyamine as a free base solution was prepared by the addition of triethylamine (9.8 mL, 64 mmol) to a solution of N-hydroxyamine HCl salt (4.4 g, 64 mmol) in DMSO (40 mL), stirred at room temperature for 5 min, filtered, and rinsed with THF. The reaction was heated in a sealed vial in an oil bath at 80° C. overnight. The reaction was diluted with ethyl acetate (200 mL) washed with aqueous saturated ammonium chloride (200 mL) and brine (200 mL). The water layer was extracted with ethyl acetate (200 mL) and the resulting second organic layer was washed with brine (200 mL). The organic layers were combined, dried over sodium sulfate, and concentrated to give 4-(N-hydroxycarbamimidoyl)-cyclohexanecarboxylic acid methyl ester (770 mg, 60%) as a white solid. LCMS calcd for C9H16N2O3 (m/e) 200, obsd 201 (M+H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:23]1[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=1)[OH:22]>N1C=CC=CC=1.ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[C:16](=[O:21])[C:15]2([C:23]1[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=1)[O:22][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3]
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ncccc1C1(OC(=O)Oc2ccccc2)C(=O)N(C(=O)Oc2ccccc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
2.6 ml (21 mmol) of phenyl chloroformate were slowly added dropwise to a solution, cooled to 0° C., of 3.00 g (9.8 mmol) of 5-chloro-3-(2-ethoxypyridin-3-yl)-3-hydroxy-1,3-dihydroindol-2-one from example a.1 in 10 ml of pyridine, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with water. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was stirred with diethyl ether. 2.58 g of the title compound were obtained as a white solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[N:15]1([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[C:29]([O:36][C@@H:37]([C@H:39]4[CH2:43][NH:42][C:41](=[O:44])[CH2:40]4)[CH3:38])[C:30]4[N:31]([N:33]=[CH:34][CH:35]=4)[CH:32]=3)=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[C:1]([N:18]1[CH2:17][CH2:16][N:15]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[N:28]=[C:29]([O:36][C@@H:37]([C@H:39]4[CH2:43][NH:42][C:41](=[O:44])[CH2:40]4)[CH3:38])[C:30]4[N:31]([N:33]=[CH:34][CH:35]=4)[CH:32]=3)=[CH:25][CH:26]=2)[CH2:20][CH2:19]1)(=[O:3])[CH3:2]
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cn2nccc12)[C@H]1CNC(=O)C1
Reactant: CC(=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(-c3cn4nccc4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
Acetic anhydride (5 μl, 0.05 mmol) was added to a solution of (R)-4-((R)-1-(6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.44 (22.38 mg, 0.04 mmol) and triethylamine (0.05 mL, 0.33 mmol) in dichloromethane (1.8 mL) at room temperature. After 90 min, reaction mixture was loaded directly onto silica gel and purified (0-8% methanol/dichloromethane) to yield (R)-4-((R)-1-((6-(4-(4-acetylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.45 (17.1 mg).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5][N:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:7]=1[Cl:8].CN(C)C=O.O.[SH-:23].[Na+]>C(OCC)C>[C:9]([N:6]1[C:7]([Cl:8])=[C:3]([CH2:2][SH:23])[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: [SH-]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(CBr)c1Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1nc(C(F)(F)F)c(CS)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
43.5 g (136.1 mmoles) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole was added to 300 ml of a N,N-dimethylformamide solution containing 21.8 g (272.2 mmoles) of sodium hydrosulfide hydrate (purity: 70%). The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water and extraction with diethyl ether was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 32.3 g (yield: 87.0%) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-metha-nethiol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:11]=2[O:10]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][C:11]=2[O:10]1
Reactant: Nc1ccc2c(c1)CCC(COC1CCCCO1)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)CCC(COC1CCCCO1)O2
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a stirred mixture of 5.3 parts of 3,4-dihydro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran-6-amine and 50 parts of pyridine were added dropwise 2.25 parts of acetic acid anhydride at a temperature below 10° C. Upon completion, stirring was continued for 10 minutes in an ice bath. The whole was stirred for 3 hours at room temperature. The reaction mixture was evaporated. Water was added to the residue. The product was extracted with 1,1'-oxybisethane. The organic layer was washed with water, dried, filtered and evaporated, yielding 5 parts (82%) of N-[3,4-dihydro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran-6-yl]-acetamide as an oily residue (intermediate 11).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:6]1[CH:10]=[CH:9][N:8]=[N:7]1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[N:1]1([C:18]2([N:6]3[CH:10]=[CH:9][N:8]=[N:7]3)[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C1CCNC1
Reactant: c1c[nH]nn1
Solvent: Cc1ccccc1
Product: c1cn(C2(N3CCCC3)CCC3(CC2)OCCO3)nn1
Temperature: 90 °C
Reaction time: 168 h

Procedure:
Pyrrolidine (1.95 g, 2.29 ml, 27.5 mmole), 1,2,3-triazole (2.07 g, 30 mmole) and molecular sieve 4 Å (7.14 g) were added to a solution of 1,4-dioxaspiro[4,5]decan-8-one (3.9 g, 25 mmole) in toluene (40 ml). The mixture was stirred for 7 days at 90° C. The solution was then decanted and immediately reacted further.
Reaction SMILES: [Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:5][N:6]=1
Reactant: Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Yield: 90.5 %

Procedure:
A solution of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (50 mg, 0.144 mmol), ethyl 2-bromo-2-methylpropanoate (22 μL, 0.144 mmol) and diisopropylethylamine (76 μL, 0.433 mmol) in DMF (1 mL) was heated to 60° C. for 20 hours. The mixture was then concentrated, sonicated in ethyl ether until fully dissolved, and washed with 1N HCl. The mixture was extracted with diethyl ether (2×5 mL), and the combined organic extracts dried over sodium sulfate, filtered, and concentrated to provide ethyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a brown oil (60 mg, 91%).
Reaction SMILES: [C:1]([NH:5][CH:6](O)[C:7]([OH:9])=[O:8])(=[O:4])[CH:2]=[CH2:3].[CH:11]1C2NC3C(=CC=CC=3)SC=2C=CC=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:36][OH:37]>C(Cl)(Cl)Cl>[CH3:36][O:37][CH:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:7]([O:9][CH3:11])=[O:8]
Reactant: CO
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: C=CC(=O)NC(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C=CC(=O)NC(OC)C(=O)OC
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a three-necked flask equipped with a stirrer and an extractor filled with a molecular sieve drying agent was added 300 parts acrylamidoglycolic acid, 3000 parts methanol, 0.05 parts phenothiazine, 4.5 parts 98% sulfuric acid and 200 parts chloroform. The mixture was heated to reflux and the distillate was allowed to pass through the extractor for 61/2 hours. The mixture was cooled and allowed to stand for 16 hours at which point the mixture was warmed to about 40° C., 19 g of sodium carbonate was added, and the solution was stirred for 21/2 hours. The mixture was filtered and vacuum stripped of solvent. The solid residue was extracted with chloroform. Diethyl ether was added to the extract and a polymeric mass precipitated which was discarded. The remaining extract was stripped of solvent to yield 264.2 parts of crude MAGME which was confirmed by chemical analysis.
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(CO)C=2)C1)(OC(C)(C)C)=O.[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][C:31]1=[O:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][C:39]=1[CH3:46]>>[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([F:37])=[C:39]([CH3:46])[CH:40]=2)[C:31]1=[O:36])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cc(CBr)ccc1F
Reactant: O=C1COCCN1Cc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Product: Cc1cc(CC2OCCN(Cc3ccccc3)C2=O)ccc1F

Procedure:
N-Benzyl-2-(4-fluoro-3-methylbenzyl)-morpholin-3-one was prepared as described for example 70, intermediate (b), but using 4-benzylmorpholine-3-one and 4-fluoro-3-methylbenzyl bromide and was isolated as a pale yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>N1C=CC=CC=1>[NH+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH+:1]1[CH:10]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2ncccc2c1
Solvent: c1ccncc1
Product: c1cc[nH+]cc1
Product: c1ccc2[nH+]cccc2c1

Procedure:
Quinolinium and pyridinium compounds were prepared by heating equimolar amounts of quinoline or pyridine with a chloro- or bromoalkyl of about 4 to about 10 carbons, or a chloro- or bromoalkylaryl of about 7 to about 20 carbons, to a temperature up to about 125° C. in about 30% aqueous alcohol. The reaction product was analyzed for free halide, and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(NC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42.7 %

Procedure:
To a solution of 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (80 mg, 0.2 mmol) and 4-amino-benzoic acid methylester (34 mg, 0.22 mmol) in N,N-dimethylformamide (4 ml) were added 4-methylmorpholine (62 mg, 0.61 mmol) and HBTU (115 mg, 0.3 mmol). The mixture was stirred for 17 h at room temperature. The reaction solution was poured in water, extracted twice with AcOEt, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (5 g silica gel, heptane/AcOEt 4:1) to give the title compound (45 mg) as a white solid. MS (m/e)=527.1 [M+H+].
Reaction SMILES: C1(C[O:8][C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:16][O:17][C:11]=3[CH:10]=2)C=CC=CC=1>C1COCC1.CCO.[Pd]>[OH:8][C:9]1[CH:26]=[CH:25][C:12]2[CH2:13][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:15][CH2:16][O:17][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(OCc3ccccc3)ccc2C1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2cc(O)ccc2C1
Yield: 100.1 %

Procedure:
1,1-Dimethylethyl 8-[(phenylmethyl)oxy]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 29) (7.35 g, 20.68 mmol) in a mixture of THF (40 ml) and EtOH (40 ml) was hydrogenated with 10% palladium on carbon (0.735 g, 6.91 mmol) for 18 hours then filtered and evaporated to give the title compound (5.49 g) as a white solid. MS (ES) C14H19NO4 requires 265; found 166 [M+H−100]+.
Reaction SMILES: [CH3:1][CH:2]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9][CH:8]([NH:23][C:24]([O:26]CC2C=CC=CC=2)=[O:25])[C:7]1=[O:34])[C:3]([OH:5])=O.S(Cl)(Cl)=O.[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40].[C:44]1([CH3:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:44]1([CH2:50][O:26][C:24](=[O:25])[NH:23][CH:8]2[N:9]=[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:6]([CH:2]([CH3:1])[C:3]([N:41]([CH2:42][CH3:43])[CH2:39][CH3:40])=[O:5])[C:7]2=[O:34])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCNCC
Reactant: Cc1ccccc1
Reactant: CC(C(=O)O)N1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)C(C)N1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Temperature: 90 °C
Reaction time: 2 h

Procedure:
390 mg (0.853 mmol) of 2,3-dihydro-alpha-methyl-2-oxo-5-phenyl-3-((phenylmethoxy)carbonyl)amino-1H-1,4-benzodiazepine-1-acetic acid was suspended in 28 ml toluene, treated with 1.07 ml (14.6 mmol) thionyl chloride, and stirred at 90° C. for 2 hours. The solvent was removed in vacuo and the residue treated with fresh toluene. The cycle was repeated 4 times. The resulting brown oil was dissolved in 5 ml THF, treated with 185 μl (1.79 mmol) of diethylamine and stirred at room temperature for 1 hour. The solvent was removed in vacuo, treated with 10% Na2CO3 solution and extracted (3x EtOAc). The extracts were combined, washed (1x H2O, 1x brine), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (10% Et2O in CH2Cl2) gave the title compound which was crystallized from Et2O: m.p. 170°-171° C.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=O)=[N:14][CH:15]=1>O.CO>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:7][OH:8])=[N:14][CH:15]=1
Reactant: NO
Reactant: O=C(Cc1ccc(Cl)cn1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=C(Cc1ccc(Cl)cn1)c1ccc(F)cc1
Yield: 98.9 %

Procedure:
Sodium acetate (6.47 g) and hydroxylamine hydrochloride (5.74 g) were dissolved in water (45 ml) and added to a solution of 2-(5-chloropyridin-2-yl)-1-(4-fluorophenyl)ethanone (3.39 g, 13.6 mmol) in methanol (200 ml). After heating at reflux for 2 h, the cooled reaction mixture was partitioned between water and ethyl acetate and the organic phase dried and concentrated to give the title compound as a yellow solid (3.56 g, 98%). NMR (CDCl3) δ 4.35 (2H, s, CH2); 7.02 (2H, t, 8 Hz, arom); 7.25 (1H, d, J 9 Hz, arom); 7.53 (1H, dd, J 9 & 2 Hz, arom); 7.71 (2H, m, arom); 8.12 (1 H, br s, OH); 8.48 (1H, s, 2 Hz, arom); Tlc SiO2 cyclohexane:ethyl acetate (3:1) Rf 0.42 detection uv254.