Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](=[O:27])[NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1ccccc1-c1ccncc1
Product: O=C(COCC(=O)Nc1ccccc1-c1ccncc1)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 1-(ii), 2-pyridin-4-yl-phenylamine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-oxo-2-([2-(pyridin-4-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 22%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:9]2[CH2:10][C:11]3[CH:35]=[CH:34][CH:33]=[CH:32][C:12]=3[N:13]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:14][C:8]2=[CH:7][CH:6]=1)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1.O>CS(C)=O>[OH:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][CH2:39][NH:38][C:3]([C:5]2[N:9]3[C:8]([CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[C:19]([CH3:31])[CH:18]=4)=[O:16])[C:12]4[CH:32]=[CH:33][CH:34]=[CH:35][C:11]=4[CH2:10]3)=[CH:7][CH:6]=2)=[O:4])=[CH:42][CH:43]=1
Reactant: NCCc1ccc(O)cc1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc(O)cc4)n3Cc3ccccc32)cc1C
Yield: 94.7 %

Procedure:
The 2,2,2-trichloro-1-[10-(2′-methoxy-2-methyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-3-yl]-ethanone of step D (0.175 g; 0.316 mmol) and tyramine (0.087 g; 0.632 mmol) were stirred in 3 mL of dimethylsulfoxide under a nitrogen atmosphere at 80° C. for 18 hours. The solution was cooled and 15 mL water were added. The resulting solid was filtered and dried to provide the title compound (0.171 g, 94%), m.p. 138-147° C. MS [(+)ESI, m/z]: 572.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:22]2[CH2:23][CH2:24][CH2:25][C:20]([OH:26])([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=3)[CH2:21]2)=[O:6])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
The compound of Example 7 was prepared according to the general preparation protocol A from 3,4-dichlorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][C@H:10]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CNCC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 6 h
Yield: 96.7 %

Procedure:
cis-4-t-Butyloxycarbonylamino-1-benzyl-3-methylpiperidine (13 g, 0.042 mol) was dissolved in 170 ml methanol and transferred to the Parr pressure reactor after addition of 1.3 g of Pd(OH)2 on carbon. The rqcytoion mixture stirred for 6 hrs at 400 psi pressure at 50° C. Catalyst was removed by filtration and evaporation of the solvent afforded 8.7 g (95%) of titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.CCCCCC>C(OCC)(=O)C.CO.[C].[Pd]>[Cl:1][C:2]1[C:3]([CH:14]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(C(F)(F)F)cc2)c(Cl)cn1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(C(F)(F)F)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
In a mixed solvent of ethyl acetate (3 ml) and methanol (3 ml) was dissolved methyl(E)-3-[5-chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylsulfonyl)methyl]pyridin-2-yl]acrylate (110 mg, 0.21 mmol). To the resulting solution was added 10% palladium-carbon catalyst (60 mg). Under a hydrogen atmosphere, the resulting mixture was stirred at room temperature for 2 hours. After the catalyst was removed by Celite filtration, the filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (94 mg, 0.18 mmol, 85%) as a white solid.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:13])([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[N+:14](=[CH2:16])=[N-:15].N(NC(N)=O)=O>CCOCC>[N+:14](=[CH:16][C:10]([C:7]1([CH3:13])[CH2:8][CH2:9][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)=[O:11])=[N-:15]
Reactant: CC(C)C1CCC(C)(C(=O)Cl)CC1
Reactant: C=[N+]=[N-]
Agent: NC(=O)NN=O
Solvent: CCOCC
Product: CC(C)C1CCC(C)(C(=O)C=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Subsequently at room temperature, 5.0 g of the 4-isopropyl-1-methylcyclohexylcarbonyl chloride was added dropwise to 150 ml of an ether solution of diazomethane prepared from 15 g of nitrosourea, and the mixture was stirred at room temperature for about 2 hours. The solvent was distilled off from the reaction mixture in a vacuum, quantitatively giving pale yellow oily 1-diazo-2-(4-isopropyl-1-methylcyclohexyl)-2-ethanone (cis:trans=1:1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.COC1C2C=NC([NH:45][C:46]([NH:48][C@@H:49]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH3:50])=[O:47])=CC=2N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)N=1>>[CH:8]([C:6]1[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:4]=2[CH:3]=[C:2]([NH:45][C:46]([NH:48][C@@H:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH3:50])=[O:47])[N:7]=1)=[O:9]
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C=O)c12

Procedure:
(R)-1-(4-Formyl-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea was prepared from Intermediate 11B using the same procedure described for (R)-1-(3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 40, Step 2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12](S(C2C=NC=CC=2)(=O)=O)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:30]2[CH:29]=[CH:28][C:27]([F:26])=[CH:32][C:31]=2[F:33])[NH:12][CH:11]=1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(F)cc1F
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: [Na+]
Product: CN(Cc1c[nH]c(-c2ccc(F)cc2F)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2,4-difluorophenyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 113 mg, 50%).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH2:10]([N:12]=[C:13]=[S:14])[CH3:11]>C(#N)C>[CH2:10]([NH:12][C:13]([N:6]1[CH2:7][CH2:8][C:9]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:5]1)=[S:14])[CH3:11]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CCN=C=S
Solvent: CC#N
Product: CCNC(=S)N1CCc2[nH]cnc2C1

Procedure:
A solution of 1.85 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 2 g of ethyl isothiocyanate in 15 ml of acetonitrile are refluxed for 7 h. The solution is cooled and filtered: 2.5 g of 5-[N-ethyl-thiocarbamoyl]-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 185°, are collected.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[S:8]1[CH2:14][C:12](=[O:13])[NH:11][C:9]1=[S:10].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH2:6]([N:11]1[C:12](=[O:13])[CH2:14][S:8][C:9]1=[S:10])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccco1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CSC(=S)N1Cc1ccco1

Procedure:
To a solution of 2-furaldehyde (43 mL) in hot glacial acetic acid (340 mL) was added rhodanine (68.4 g) and sodium acetate (128.4 g). The solution was refluxed for 0.5 hour and poured into water (2.6 L). The precipitate was collected by filtration and washed with water (1.4 L), ethanol (500 mL), and diethyl ether (200 mL). Recrystallization from acetone gave furfuryl rhodanine (97.4 g). The structure of the product was confirmed by NMR.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:22])([CH3:21])[C:15]#[C:16][CH:17]=[CH:18][CH:19]=O.[BH4-].[Na+]>C(OCC)C.CO>[CH3:13][C:14]([CH3:22])([CH3:21])[C:15]#[C:16][CH:17]=[CH:18][CH2:19][NH:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)C#CC=CC=O
Reactant: NCc1cccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)C#CC=CCNCc1cccc2ccccc12

Procedure:
A mixture of 1-naphthalenemethanamine (1.34 g, 8.51 mmol) and 6,6-dimethyl-2-hepten-4-ynal (1.16 g, 8.51 mmol) in 20 ml of dry ethyl ether was stirred over 4A sieves overnight. Sieve material was then removed by centrifugation, washed once with ethyl ether and the combined ether fractions concentrated to afford the crude condensed product. About 8.08 mmol of this material was stirred with sodium borohydride (343 mg, 9.06 mmol) in 20 ml of methanol at room temperature for 3.75 hours. The reaction mixture was partitioned between aqueous sodium bicarbonate and methylene chloride, the aqueous layer extracted twice with methylene chloride, and the combined organic solution washed with water and dried over magnesium sulfate. Removal of the solvent afforded N-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine as a mixture of the E and Z isomers. Flash chromatography of this product on silica gel (5 cm column, eluting with 0.2% triethylamine in chloroform) afforded 0.74 g of the pure (E)-N-6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[OH-].[Na+]>C(O)C>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:12]([F:13])([F:14])[F:15])=[C:3]([F:2])[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)c(F)c1

Procedure:
To a solution of 20 ml of concentrated hydrochloric acid and 15 ml of 95% ethanol is added 5.0 g (24 mmole) of 2-fluoro,4-nitrobenzotrifluoride. The mixture is stirred and 20 g (88 mmole) of stannous chloride dihydrate is added in portions over a 30 min period. The reaction is exothermic and during the addition the temperature is maintained at 60°. When the addition is complete, the mixture is stirred at 60° for an additional 30 min. The reaction is cooled and poured onto a mixture of ice and 36% sodium hydroxide, which is extracted with ether (3×). The combined ether layers are washed once with brine and dried over sodium sulfate. Filtration and evaporation of the solvent gave 4-amino,2-fluorobenzotrifluoride (3-fluoro-4-trifluoromethylaniline).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:29]1(=[O:35])[NH:33][C:32](=[O:34])[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CC(O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:13]2[C:14]([CH3:17])([CH3:18])[C:15](=[O:16])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:33]4[C:29](=[O:35])[CH2:30][CH2:31][C:32]4=[O:34])[CH2:6][CH2:7]3)[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
7.4 g 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A1) and 3.6 g succinimide are suspended in 50 ml of 2-propanol and heated to 50° C. 5.1 g potassium carbonate are added in portions during 1 h. After adding potassium carbonate the reaction mixture is stirred for 30 min at 50° C., then 3-4 h at 75° C. until the reaction is complete. After stirring for 3-4 h at 75° C., the heating is turned off and the mixture is allowed to cool down slowly to RT. 100 ml of water is added, the mixture is stirred for 0.5 h at RT and the crystallized product is filtered. The product is dried at 50° C. in a vacuum dryer.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[CH:17]1([CH:20]=O)[CH2:19][CH2:18]1.OOS([O-])=O.[K+]>CN(C=O)C.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:20]([CH:17]3[CH2:19][CH2:18]3)[N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: O=CC1CC1
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nccc(-n2c(C3CC3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (400 mg, 1.43 mmol) in DMF (4 mL) were added cyclopropanecarbaldehyde (130 mg, 1.86 mmol) and oxone (527 mg, 0.86 mmol). The reaction was stirred at RT for 3 days. The mixture was diluted with EtOAc (20 mL) and washed with water. The aqueous layer was extracted with more EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (Isolute column, 100% DCM to 2% MeOH/DCM) afforded the title compound as an orange solid: 1H NMR (500 MHz, MeOD) δ 1.16-1.24 (2H, m), 1.24-1.29 (2H, m), 2.32-2.48 (1H, m), 6.98 (1H, d, J=5.36 Hz), 7.41-7.45 (1H, m), 7.47-7.52 (1H, m), 7.90 (1H, d, J=1.89 Hz), 8.51 (1H, d, J=5.20 Hz); LC-MS (Method B): m/z=+330.0, 331.8 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH:8]2[CH:10]([OH:11])[CH:4]([CH2:5][N:6]([CH3:12])[CH2:7]2)[CH2:3]1.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH:4]2[CH:10]([O:11][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]([CH2:9][N:2]([CH3:1])[CH2:3]2)[CH2:7]1
Reactant: ClCc1ccccc1
Reactant: CN1CC2CN(C)CC(C1)C2O
Product: CN1CC2CN(C)CC(C1)C2OCc1ccccc1
Yield: 32.4 %

Procedure:
18.3 g of 3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane-9-ol are reacted with 13.5 g of benzyl chloride for 4 hours at room temperature as described in Example 1. 9 g (32.3%) of 3,7-dimethyl-9-benzyloxy-3,7-diazabicyclo[3.3.1]nonane are obtained; b.p.: 137°-148° C./10 Pa. The free base rapidly crystallizes upon standing; m.p.: 70°-75° C.
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:12]([N:15]=[C:2]([CH3:4])[C:1](=[O:5])[NH:16]2)=[CH:13][CH:14]=1
Reactant: CC(=O)C(=O)O
Reactant: COc1ccc(N)c(N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2nc(C)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.8 %

Procedure:
Pyruvic acid (60 mL, 868 mmol, 1.2 eq) is added at room temperature to a stirred suspension of 4-methoxy-benzene-1,2-diamine (100 g, 724 mmol, 1.0 eq) in 1.8M sulfuric acid aqueous solution (1000 mL). After 24 hours stirring at room temperature, the reaction mixture is neutralized by the addition of 1N sodium hydroxide aqueous solution. The resulting precipitate is filtered and washed with water to afford 7-methoxy-3-methyl-1H-quinoxalin-2-one as a dark purple solid (125 g, 91% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:13]1([NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A mixture of ethyl 3-aminobenzoate (0.200 g; 1.21 mmol), benzeneboronic acid (0.295 g; 2.42 mmol), copper acetate (0.439 g; 2.42 mmol) and pyridine (0.196 mL; 2.42 mmol) in dichloromethane (8 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent 5 to 35% ethyl acetate in heptane) to yield 0.255 g (87%) of the title compound as a yellow oil.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH3:15])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=2)[CH2:58][CH2:59][CH2:60][NH2:61])=[CH:53][CH:52]=1>CN(C=O)C.C(OCC)C>[F:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]([C:62]2[CH:63]=[CH:64][C:65]([F:68])=[CH:66][CH:67]=2)[CH2:58][CH2:59][CH2:60][NH:61][C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH3:15])=[O:14])=[CH:53][CH:52]=1
Reactant: C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)N1CCCCCC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 65.6 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-propanoic acid (0.300 g, 1.40 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.732 mL, 4.20 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.531 g, 1.40 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.412 g, 1.40 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 40 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (70% EtOAc in hexanes) to afford 0.42 g (65%) of the pure titled compound as a white foam: mp 29-49° C. APCI-MS m/z 458.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH:12]([NH:15][OH:16])([CH3:14])[CH3:13]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:15]([CH:12]([CH3:14])[CH3:13])[O-:16])[CH3:2]
Reactant: CCOc1ccccc1C=O
Reactant: CC(C)NO
Product: CCOc1ccccc1C=[N+]([O-])C(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 2-ethoxybenzaldehyde and N-isopropylhydroxylamine. The title compound was isolated in 48.8% yield as a solid, m.p. 59.4° C. (Rf=0.48 on a silica gel plate using ethyl acetate as the eluant).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19])=[O:24]
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (250 mg, 0.93 mmol) was suspended in methylene chloride (10 ml) and treated with o-chlorobenzoylchloride (0.124 ml, 0.97 mmol) followed by triethylamine (0.143 ml, 0.97 mmol). The solution was stirred at room temperature overnight. The reaction solution was chromatographed on silica gel (chloroform followed by 97/3 chloroform/methanol) and the combined product fractions were evaporated to dryness in vacuo. TLC: Silica gel (90:10:1, CHCl3 :CH3OH:H2O), Rf =0.85.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH:4]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]2)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([O:12]C)[C:6]=1[F:14].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[Cl:1][CH2:2][C:3]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH:4]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]2)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([OH:12])[C:6]=1[F:14]
Reactant: COc1c(F)ccc(C(Nc2cccc3nc(C)ccc23)C(O)(CCl)C(F)(F)F)c1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc2c(NC(c3ccc(F)c(O)c3F)C(O)(CCl)C(F)(F)F)cccc2n1
Reaction time: 16 h
Yield: 87.5 %

Procedure:
To 50 mg (0.11 mmol) of α-Chloromethyl-2,4-difluoro-3-methoxy-β-[(2-methylquinolin-5-yl)amino]-α-(trifluoromethyl)benzeneethanol in 4.9 dichloromethane at 0° C. are added 2.1 ml of a 1 M solution of boron tribromide in dichloromethane under argon. The reaction mixture is stirred for 16 hours in a temperature range of between 0° C. and 25° C. The reaction mixture is mixed at 0° C. with saturated sodium bicarbonate solution. After dilution with ethyl acetate the batch is allowed to come to room temperature, stirred for 10 minutes and extracted twice with ethyl acetate. The combined organic extracts are washed with saturated NaCl solution and dried over sodium sulfate. The solvent is partially evaporated and the remaining residue is passed through a short path of silica gel (ethyl acetate 100%). 43 mg of the desired compound are isolated.